title: Comparisons of the influenza virus A M2 channel binding affinities, anti-influenza virus potencies and NMDA antagonistic activities of 2-alkyl-2-aminoadamantanes and analogues.
abstract: The new 2-alkyl-2-aminoadamantanes and analogues 4-10 were designed and synthesized by simplification of the structure of the potent anti-influenza virus A spiranic aminoadamantane heterocycles 2 and 3. The aim of the present work was to examine the effects of bulky and extended lipophilic moieties attached to amantadine 1 on binding to the M2 channel and the resulting antiviral potency. The binding affinities of the compounds to the M2 protein of influenza virus A/chicken/Germany/27 (Weybridge strain; H7N7) were measured for the first time using an assay based on quenching of Trp-41 fluorescence by His-37 protonation, and their antiviral potencies were evaluated against the replication of influenza virus A H2N2 and H3N2 subtypes and influenza virus B in MDCK cells. Of the various 2-alkyl-2-aminoadamantanes, and analogues, spiro[piperidine-2,2'-adamantane] 3 had the strongest M2 binding and antiviral potency, which were similar those of amantadine 1. The relative binding affinities suggested that the rigid carbon framework provided by the pyrrolidine or piperidine rings results in a more favorable orientation inside the M2 channel pore as compared to large, freely rotating alkyl groups. The aminoadamantane derivatives exhibited similar NMDA antagonistic activity to amantadine 1. A striking finding was the antiviral activity of the adamantanols 4, and 6, which lack any NMDA antagonist activity.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupolis-Zografou, GR-15771 Athens, Greece. ankol@pharm.uoa.gr
authors.forename: Antonios
authors.initials: A
authors.lastname: Kolocouris
authors.forename: Philip
authors.initials: P
authors.lastname: Spearpoint
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Hay
authors.forename: Marta
authors.initials: M
authors.lastname: López-Querol
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Sureda
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Padalko
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000547:Amantadine / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects*; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014763:Viral Matrix Proteins / Q000187:drug effects*; D000086082:Viroporin Proteins
chemical_list: D000218:Adamantane; D000547:Amantadine; D000998:Antiviral Agents; D016202:N-Methylaspartate; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins